ESCAPE-NA1 Trial: Nerinetide Neuroprotection During EVT for Acute Ischemic Stroke
In patients with LVO stroke undergoing EVT within 12 hours with favorable imaging, does a single IV dose of nerinetide improve functional independence (mRS 0-2) at 90 days compared with placebo?
Hill et al. (Lancet 2020) · doi:10.1016/S0140-6736(20)30258-0 · 1105 patients
Population
Included
- Age 18 or older
- Acute ischemic stroke with anterior-circulation LVO (intracranial ICA or M1)
- EVT eligible and planned within 12 hours of last known well
- ASPECTS 5 or greater or equivalent favorable perfusion imaging
- Pre-stroke mRS 0-1
Clinical
- Adults aged 18 years or older
- A disabling ischaemic stroke at the time of randomisation (National Institutes of Health Stroke Scale [NIHSS] score >5; range 0 to 42, with higher scores indicating greater stroke severity)
- Functioning independently in the community before the stroke (Barthel Index score >90; range 0 to 100, with higher scores indicating a greater ability to complete activities of daily living)
- Enrolled up to 12 h after the onset of stroke symptoms (time the patient was last seen well)
Imaging
- A confirmed proximal intracranial artery occlusion on non-contrast CT and multiphase CT angiography, defined as an occlusion of the intracranial internal carotid artery, the first segment of the middle cerebral artery, or both
- A small-to-moderate ischaemic core, defined as an Alberta Stroke Program Early CT Score (ASPECTS) of 5 to 10 with 1 point subtracted for any evidence of early ischaemic change in each defined region on the CT scan
- Moderate-to-good collateral circulation, defined as the filling of 50% or more of the middle-cerebral-artery pial arterial circulation on CT angiography
Excluded
- ASPECTS below 5 on baseline CT
- Pre-stroke mRS 2 or greater
- Contraindication to contrast or study drug
- Large intracranial hemorrhage on baseline imaging
- Pregnant or breastfeeding
- NIHSS score of 5 or less (non-disabling deficit)
- Pre-stroke Barthel Index of 90 or below (not functioning independently in the community before the stroke)
- ASPECTS below 5 on baseline non-contrast CT
- Absence of a proximal anterior-circulation occlusion (intracranial internal carotid artery or first segment of the middle cerebral artery) on CT angiography
- Poor collateral circulation (less than 50% middle-cerebral-artery pial filling)
- More than 12 h from the time the patient was last seen well
- Contraindication to iodinated contrast or to the study drug
- Pregnancy or breastfeeding
Source: Hill MD et al., Lancet 2020;395(10227):878–887; NCT02930018· Retrieved 2026-06-09
Primary Outcome — Functional Independence (mRS 0-2) at 90 Days
1105 patients; nerinetide vs placebo before or during EVT within 12 hours
Small absolute difference — interpret with caution
Functional Independence (mRS 0-2) at 90 Days
Study Arms
- Agent
- Nerinetide (Tat-NR2B9c; eicosapeptide PSD-95 inhibitor)
- Dose
- 2.6 mg/kg, up to a maximum of 270 mg (based on estimated or actual weight)
- Route
- IV (single dose, dedicated intravenous line)
- Frequency
- Single dose, administered as soon as possible after randomisation
- Duration
- Infused over 10 min (a difference of plus or minus 1 min allowed)
- Co-interventions
- Rapid endovascular thrombectomy using available devices in all patients; intravenous alteplase given before or during EVT according to usual care and national or regional guidelines, at the discretion of the treating team (alteplase was not a requirement)
Sites were asked to ensure the study drug was administered before arterial access closure. The trial was negative overall: functional independence (mRS 0 to 2) at 90 days was 61.4% with nerinetide versus 59.2% with placebo (adjusted risk ratio 1.04, 95% CI 0.96 to 1.13, p=0.35). A prespecified interaction suggested differential effect in patients not receiving alteplase, which is hypothesis-generating only.
- Agent
- Saline placebo
- Dose
- Volume-matched to the nerinetide dose
- Route
- IV (single dose, dedicated intravenous line)
- Frequency
- Single dose, administered as soon as possible after randomisation
- Duration
- Infused over 10 min
- Co-interventions
- Rapid endovascular thrombectomy using available devices in all patients; intravenous alteplase per usual care, identical to the active arm. Nerinetide and placebo were prepared as colourless solutions in numbered, refrigerated vials that were visually identical except for a unique vial number, so all trial personnel and patients were fully masked
Mortality and symptomatic intracranial haemorrhage rates were similar between groups. Eligibility was restricted to anterior-circulation large-vessel occlusion only; posterior-circulation occlusions were not enrolled.
Trial Design
Type
- Multicenter double-blind placebo-controlled randomized trial
- All patients underwent thrombectomy for large-vessel occlusion
- Treatment window up to 12 hours with favorable imaging selection
- Stratified by alteplase use and declared first EVT device
Timeline
48 hospitals in 8 countries
N
1105
Enrollment
1105 patients at 48 hospitals across 8 countries. Double-blind placebo-controlled randomized trial. Single IV nerinetide dose before or during EVT. Treatment window up to 12 hours with favorable imaging. Published Lancet 2020.
ClinicalTrials.gov
NCT02930018Bedside Pearl
ESCAPE-NA1 was negative overall for nerinetide in EVT patients. The alteplase-free subgroup signal is hypothesis-generating only; do not alter thrombolysis decisions or advocate for nerinetide use based on this finding. Neuroprotection after EVT remains unproven.
See also